Assessment of pharmacology and potential anti-obesity properties of H3 receptor antagonists/inverse agonists

Histamine is a key neurotransmitter that alters central nervous system functions in both behavioural and homeostatic contexts through its actions on the histamine (H) subreceptors H₁, H₂ and H₃ G-protein-coupled receptors. H₃receptors have a diverse central nervous system distribution where they function as both homo- and hetero-receptors to modulate the synthesis and/or release of several neurotransmitters. H₃ receptors are constitutively active, which implies that antagonists of H₃ receptors may also function as inverse agonists to alter the basal state of the receptor and uncouple constitutive receptor–G-protein interactions. Reference H₃ antagonists such as thioperamide and ciproxifan, administered either centrally or systemically, have been shown to cause changes in food consumption and/or body weight in proof-of-concept studies. More recently, several non-imidazole-based H₃ antagonists/inverse agonists have also been described with efficacy in at least one animal model of human obesity. Considerable preclinical effort remains necessary before such compounds achieve therapeutic success or failure. Moreover, ongoing research in a number of laboratories has shed new insights into the effects of H₃ ligands in the control of feeding, appetite and body weight, which offer different results and conclusions. The goal of this review is to appraise these findings and forecast whether any H₃ antagonists/inverse agonists will provide clinical utility to treat human obesity.